Implantation in humans of xenogeneic tissue, i.e. tissue from a species other than human, has been carried on extensively for more than two decades. Xenogeneic implants are useful in replacing human tissues which are damaged by pathological or traumatic injury. Such implants have been used for replacing heart valves, ligaments, tendons and skin, for example. Many techniques for preparation and treatment of xenogeneic tissue have been developed for many types of prosthetic and tissue repair applications in the human body. For example, treatment of such tissue with collagen in various forms and degrees of denaturization are known (U.S. Pat. Nos. 3,563,228, Seiderman, 3,949,073, Daniels et al, and 4,233,360, Luck, et al.) Treatment of graft tissues with aldehydes, and glutaraldehyde in particular, is well known (see, for example, U.S. Pat. No. 3,988,872, Dardik, et al, which is but one of many disclosures of the use of glutaraldehyde in tissue treatment.)
Exemplary of the state of the art are the following U.S. Pat. Nos.: Angell et al., U.S. Pat. Nos. 4,035,848 and 4,247,292 and Hancock, et al, U.S. Pat. No. 4,050,893--glutaraldehyde treatment of porcine heart valves; Schechter, U.S. Pat. No. 4,120,649--glutaraldehyde treatment of pigskin, human tissue, and amniotic membranes; Holman, et al, U.S. Pat. Nos. 4,239,492 and 4,240,794--glutaraldehyde treatment of umbilical cord tissue for vascular grafts; Ketharanathan, U.S. Pat. No. 4,319,363--glutaraldehyde treatment of artificially induced tubular structure of collagenous tissue; Lentz et al, U.S. Pat. No. 4,323,358--treatment of implant tissue with glutaraldehyde and wetting agent; Wright, U.S. Pat. No. 4,350,492, and Lane, U.S. Pat. Nos. 4,372,743 and 4,443,895--heart valve prosthesis from glutaraldehyde treated porcine heart valve; Kurland, U.S. Pat. No. 4,400,833--tendons and ligaments from cows and pericardium or other porcine tissue treated with glutaraldehyde and reinforced with synthetic mesh structure; Pollock, et al, U.S. Pat. No. 4,402,697--treatment of implant tissue with phosphate ester and glutaraldehyde; and Pollock, U.S. Pat. No. 4,405,327--treatment of implant tissue with quaternary ammonium compounds and glutaraldehyde.
One of the major problems which have had to be overcome in the preparation of implant tissues is the histocompatibility barriers which the human recipient erect when a non-self material is introduced. Immune rejection of transplants has been and remains a concern, even though much work has been done in this area of medical-immunochemical technology.
Prevention of or inhibition of infection is another goal in the field of implantation.
As illustrated by the previously cited prior art, glutaraldehyde has been reported as being effective in reducing antigenicity and inhibiting infection of implant tissue. Glutaraldehyde cross-links proteins rapidly and effectively, and causes the cross-linking of proteins in the tissue being treated. This treatment increases resistance to proteolytic cleavage and hence increases resistance to enzymatic degradation. The treatment of implant tissue with glutaraldehyde is sometimes referred to as "tanning" because it crosslinks the protein and inhibits enzymatic and biochemical degradation of the tissue, comparable in general to the effect of tanning leather. Glutaraldehyde is also often used as the preservative in aqueous solution for storing tissues after treatment.
Xenografts prepared by the prior art methods suffer from three principal disadvantages, none of which precludes their use for human implantation, but which, nevertheless, represent deterrents to their greater acceptability for use in human tissue replacement.
First, despite the fact that their primary constituent is only weakly immunogenic, by virtue of collagen being present in all mammalian species, and that the crosslinking process further reduces their immunogenicity, xenografts are capable of stimulating the formation of circulating antibodies in the human system, indicating some residual immunogenicity.
Second, the use of some chemical sterilants increases the risk that toxic response will be encountered in sensitive individuals, even after thorough rinsing of the xenograft prior to implantation.
Third, crosslinked xenografts are somewhat stiffer than the native tissue and this stiffness, or lessened compliance, is undesirable, since the xenograft functions best when it preserves the original biomechanical properties that nature intended for the function of that particular tissue.
A feature of the present invention is that it encompasses methods of radiating pre-crosslinked tissue which reduces, or eliminates, one or all of these three disadvantages.
Collagenous tissue in uncrosslinked form has been reported to be seriously degraded by radiation. Apparently, this reported result has deterred investigators from studying all aspects of radiation treatment of xenogeneic tissue.